DEMYSTIFYING MEDICINE

FRAGILE X SYNDROME & RELATED DISORDERS

March 31, 2009

Walter E. Kaufmann

One Gene (FMR1):Three (or More) Disorders

ID, ASD, LD? Hagerman et al. Pediatrics 123:378-90, 2009

M: 1:800, F: 1:250 M: 1:4000, F: 1:6000

One Gene (FMR1):Multiple disorders in the same family

Hagerman. J Dev Behav Pediatr 27:63-74, 2006

Fragile X Syndrome:One gene, Three Major Disorders

Fragile X syndrome: in males and females with full mutation (200-2,000 repeats) or mosaicism (full mutation+premutation). Life-long disorder.

Fragile X tremor ataxia syndrome (FXTAS): predominantly older(>50 years) males with premutation (61-199 repeats). Manifestations: gait ataxia, intention tremor, cognitive impairment(frontal lobe dementia).

Premutation-related disorders: POI, females with emotionalproblems and perseverative thinking, children (mainlyboys) with ADHD, intellectual disability and/or autism.

Intermediate or gray zone (41-60 repeats) : ??

FMR1 Mutation

X-linked: Males more Affected than Females

Fragile X Syndrome

Diagnosis by FMR1 Southern blot and PCR

Cytogenetics

Kaufmann and Reiss. Am J Med Genet 88:11-24, 1999

CONT MOS FM PM

FMRP Patterns

FMRP quantifications providecomplementary information

Kaufmann et al. Am J Med Genet 83:286-295, 1999

Fragile X Phenotype

Adapted from Kaufmann & Reiss. Am J Med Genet 88:11-24, 1999

• Affects about 1:4000 males, 1:6000 females

• Neuro Phenotype (VARIABLE)– Mild/Moderate MR– ADHD– Autism– Social Withdrawal– Aggressive Behavior– Hyperarousal– Seizures

• Non-Neuro Phenotype– Facial characteristics (non-diagnostic)– Connective tissue abnormalities (joint

laxity, mitral valve prolapse)– Strabismus– Recurrent OM– GER

From Fragile X Research Foundation website

Fragile X syndrome as a Major Cause of Intellectual DisabilityPRACTICE PARAMETERS for GDD (CNS & AAN):

Shevell et al. Neurology 60:367-380, 2003.

Fragile X as a Major Cause of Intellectual Disability

Mild to Moderate ID vs. Moderate to Severe in Other Genetic Disorders

Down Syndrome Fragile X Syndrome

Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006

Capone et al. Am J Med Genet 134A:373-380, 2005Carter et al. Am J Med Genet 144B:87-94, 2007

0

10

20

30

40

50

60

70

80

% of subjects

<25 25-39 40-54 55-70

Cognitive Level (IQ)

DS+ASD DS+SMD DS Typical

0

10

20

30

40

50

60

70

80

% of subjects

<25 25-39 40-54 55-70 70+

Cognitive Level (IQ)

FXS+ASD FXS Typical

Fragile X syndrome as a Major Cause of Autism

Typical Fragile X

Schaefer & Mendelsohn. Genet Med 10:301-5, 2008/ACMG Practice Guidelines

Fragile X + Autism

KKI Research Program on Autism in FXS

Fragile X syndrome as a Major Cause of Autism

Autism in Fragile X and Down Syndromes

% VarianceIQ/DQ: 0%ABCstereo: 13%AutBehav rel: 27%

DS+ASD vs. DS Typical

ASD

ASD

ASD

IQ/DQp=0.99

ABCstereop=0.001

AutBehav relp<0.0001

FXS+ASD vs. FXS Typical

ASDIQ/DQp=0.54

ASDABClethp=0.79

ASDADIrecsp<0.0001

% VarianceIQ/DQ: 0.5%ABCleth: 0.1%ADIrecs: 53%

Low IQ per se has a minimal influence upon ASD status in ID

Autism in Fragile X

1. Delayed/impaired adaptive socialization is the primary determinant of FraX+ASD. CORTEX

Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006Hernandez et al. Am J Med Genet: in press.

16-50% prevalence of Autism/ASD in Fragile X Syndrome

Example of Research in Autism in Fragile X: Determining Behavioral Profiles

2. Severe social withdrawal (indifference) is an important secondary contributor. LIMBIC SYSTEM

16-50% prevalence of Autism/ASD in Fragile X Syndrome

Example of Research in Autism in Fragile X: Determining Behavioral Profiles

Kaufmann et al. Am J Med Genet 129A:225-234, 2004Budimirovic et al. Am J Med Genet 140A:1814-1826, 2006Hernandez et al. Am J Med Genet: in press.

Autism in Fragile X

Behavioral Features in FXS: Diagnostic ChallengesShy temperament: misdiagnosis Social Anxiety: missing diagnosis (Social Anxiety is the mostcommon psychiatric co-morbidity in “Idiopathic” Autism

• Avoidance of eye contact• Hyperactivity• Perseverative speech• Hand flapping• Distractibility

Autism in Fragile X

Roberts et al. JADD 37:1748-60, 2007

The Social Approach Scale paradigm identifies dynamics of social avoidance and indifference that can distinguish Autism from Social Anxiety in Fragile X

Autism in Fragile X

Behavioral Basis

Cognitive trajectory distinguishes FXS+ASD

Hernandez et al. Am J Med Genet: in press

Autism in Fragile X

1. Hyperplasia of the posterior-superior vermis in boys with FXS+Autism (vs. FXS Typical)(Kaufmann et al. J Child Neurol 18:463-470, 2003)

Fragile X

LOB VI-VII

LOB VIII-X

LOB I-V

LOB VI-VII

LOB VIII-X

LOB I-V

Fragile X + AUT

FXS Typical FXS+Autism

2. Abnormalities in the cytoplasmic FMR1 interacting protein 1 (CYFIP1) pathway in lymphoblasts from boys with FXS+ASD (vs. controls and dup15q):GPR155 in FXS, CYFP1 & JAKMIP1/MARLIN-1 in dup15q(Nishimura et al. Hum Mol Genet 16:1682-1698, 2007)

Biological Bases

Autism in Fragile X

Symptomatic Treatment: Specific Manifestations

CNS Stimulants: ADHD• Methylphenidate• Dextroamphetamine Alpha-adrenergic agonists: ADHD, hyperarousal• Clonidine• GuanfacineAtypical antipsychotics: Aggressive behavior, stereotypic behavior, anxiety (*)• Risperidone• Aripiprazole*Selected Serotonin Reuptake Inhibitors (SSRIs): Anxiety, autistic symptoms• Fluoxetine• Sertraline

Anticonvulsants & Mood stabilizers: Seizures, mood disorders• Carbamazepine • Valproic Acid.• Lithium Carbonate

Treatment of Fragile X

Treatment of Fragile X

Targeted Treatments: Neurobiologically-BasedMultiple Cognitive & Behavioral Symptoms

• mGluR5 antagonists: multiple ongoing trials, initial trial completed

• GABA agonists: on initial trial

• Ampakines: initial trial completed

• Lithium: initial trial completed

• Other synaptic modulators (minocycline): on initial trial

Amiri et al. Arch Neurol 65:19-25, 2008

Diagnostic and Clinical Features of FXTAS

Fragile X-Associated Tremor/Ataxia Syndrome

Courtesy of Dr. R. Hagerman

Brunberg et al. AJNR 23:1757-1766, 2002

Neuroimaging of FXTAS

MCP sign

Fragile X-Associated Tremor/Ataxia Syndrome

Amiri et al. Arch Neurol 65:19-25, 2008

Cultured neural cells: nuclear lamin IR

Normal CGG88

G

N

Neuropathology of FXTAS

Intranuclear inclusions

Fragile X-Associated Tremor/Ataxia Syndrome

Premature Ovarian Failure/Primary Ovarian InsufficiencyPOF/POI

Wittenberger et al. Fertil Steril 87:456-465, 2007

~15% of women with FMR1 premutation0.8-7.5% FMR1 premutation in sporadic POI

13% FMR1 premutation in familial POI

Wittenberger et al. Fertil Steril 87:456-465, 2007

Primary Ovarian Insufficiency

The Other Premutation-Related Disorders

Children

Farzin et al. J Dev Behav Pediatr 27:137-144, 2006

Children

Aziz et al. Am J Med Genet 121B:119-127, 2003

The Other Premutation-Related Disorders

Adults

The Other Premutation-Related Disorders

Coffey et al. Am J Med Genet 146A:1009-1016, 2008

Adult females with Premutation

The Other Premutation-Related Disorders

Fragile X Gene Related Disorders

1. Key to understanding ID and ASD.2. Contributory to neurobiology of

synaptic development andmaintenance.

3. Key to understanding RNA toxicity and formation of neuronal and glial inclusions.

4. Contributory to the clinical study of neurodegenerative disorders.

Chechlacz & Gleeson.Pediatr Neurol 29:11-17, 2003

Conclusions

The Postsynaptic Density:convergence of RTT, FXS & XLMR

XLMRs are associated to mutations in signaling and synaptic proteins

The X-linked mental retardation protein oligophrenin-1is required for dendritic spine morphogenesis.Govek et al. Nat Neurosci 7:364-372, 2004.Knock-down of OPHN1 levels in CA1 neurons in rathippocampal slices significantly decreases spine length.Reduced OPHN1 levels affect spine length by increasingRhoA and Rho-kinase activities. There is an interactionbetween OPHN1 and the postsynaptic adaptor Homer.

Chechlacz & Gleeson.Pediatr Neurol 29:11-17, 2003